JP2020056594A - Chromatograph - Google Patents

Abstract

To facilitate the handling of cases where a chromatograph does not operate properly.SOLUTION: The chromatograph (liquid chromatograph 100) for analyzing a sample by supplying an eluent solution and the sample and by separating and detecting components contained in the sample, includes a detection unit (control unit 170) that detects defects in the analyzing, and an operation control unit (control unit 170) that makes the components involved in the analyzing execute at least one of the operations for identifying a cause of the defects or for avoiding the defects from arising.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a chromatograph, and more particularly, to a technique that can facilitate appropriate operation and the like.

  As a technique that can easily perform an appropriate operation of a chromatograph, there is known a technique in which a known sample is analyzed, and when an analysis error occurs, guidance regarding a check item is displayed. Reference 1).

JP-A-4-130271

  However, if the chromatograph does not operate properly, the cause cannot always be specified from the analysis results. Even if guidance regarding the check item is displayed, the user may need to be skilled or experienced to deal with the error, and it is not always easy to operate properly.

  The present invention has been made in view of the above points, and has as its object to make it easy to deal with a case where a chromatograph does not operate properly.

To achieve the above objectives,
The first invention is
A chromatograph for supplying an eluent and a sample, analyzing the sample by separating and detecting components contained in the sample,
A detection unit that detects a defect in the analysis,
An operation control unit that causes the component related to the analysis to perform at least one of the operation for identifying the cause of the failure or the operation for avoiding the failure,
It is characterized by having.

  As a result, various defects in the analysis of the sample are detected, and an operation for identifying the cause of the defect and an operation for avoiding the defect are performed, thereby coping with a case where the chromatograph does not operate properly. Can be facilitated.

  According to the present invention, it is possible to easily deal with a case where the chromatograph does not operate properly.

It is a block diagram showing a schematic structure of a chromatograph. FIG. 3 is a block diagram schematically illustrating a functional configuration of a control unit 170. It is explanatory drawing which shows some examples of a chromatogram. It is explanatory drawing which shows some examples of another chromatogram. It is explanatory drawing which shows some examples of another chromatogram. It is explanatory drawing which shows some examples of another chromatogram. It is explanatory drawing which shows some examples of another chromatogram. It is a flowchart which shows the operation | movement of a chromatograph.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings.

(Configuration of Liquid Chromatograph 100)
FIG. 1 shows a schematic configuration of a liquid chromatograph 100. The liquid chromatograph 100 includes a pump 110 (gradient pump) for sending an eluent supplied from an eluent tank 112 via a valve 111, an autosampler 120 for injecting a sample (not shown), and having an automatic purging function. And guard columns 132 and 133 (or pre-columns) which are switchably provided via a six-way valve 131, a separation column 142 which is provided detachably via a six-way valve 141, and the temperature of the separation column 142 is detected. , A temperature sensor 143 and a column thermostat 144 to be controlled, a reactor 152 detachably provided via a six-way valve 151, a detector 160 for detecting components in the separated sample, and a liquid chromatograph 100. The control unit 170 (the detection unit, the operation control Part) and a. In addition, one or more (in) line filters may be provided so as to be detachable or switchable together with or instead of the guard columns 132 and 133, and may be similarly controlled. The type of the reactor 152 is not particularly limited, and for example, a cartridge type reactor, a reaction column, a reaction coil, and the like can be applied.

  The control unit 170 is, for example, based on the pump pressure detected by the pressure sensor 113, the temperature of the separation column 142 detected by the temperature sensor 143, and the detection result of each component in the sample by the detector 160, In addition to detecting an abnormality such as an abnormal increase in pump pressure or a failure in detecting each component, each unit is caused to perform an operation for identifying a factor of the abnormality and an operation for avoiding the abnormality. More specifically, the control unit 170 includes, for example, an inference engine 170a as shown in FIG. 2, and according to input signals input from the pressure sensor 113, the temperature sensor 143, and the detector 160, the knowledge data storage unit 170b The operation of the six-way valves 131 to 151, the column thermostat 144, and the pump 110 is adjusted based on knowledge data obtained from the communication unit 170c. Hereinafter, a specific example will be described.

(Identify the cause of pump pressure abnormality and avoid abnormality)
If the pump pressure detected by the pressure sensor 113 rises abnormally, the control unit 170 controls the switching of the six-way valves 131 to 151 in order as shown in, for example, (Table 1) below to determine the cause of the pump pressure rise. Identify.

  For example, first, the guard columns 132 and 133 are switched from one to the other by the six-way valve 131. As a result, if the pump pressure is reduced to an appropriate pressure, it is specified that the cause of the problem is the guard columns 132 and 133, and the above problem is avoided, so that subsequent detection can be performed appropriately. become.

  In addition, if the pump pressure does not decrease even when the guard columns 132 and 133 are switched, the reactor 152 is separated from the liquid sending flow path by the six-way valve 151 next. As a result, if the pump pressure decreases to an appropriate pressure, it is determined (estimated) that the cause of the malfunction was the reactor 152. In this case, for example, a message prompting replacement of the reactor 152 is displayed on a display unit (not shown), and if the user replaces the reactor 152, subsequent detection can be performed appropriately.

  Furthermore, if the pump pressure does not decrease even when the reactor 152 is separated, the separation column 142 is separated from the liquid sending flow path by the six-way valve 141. As a result, if the pump pressure is reduced to an appropriate pressure, the cause of the failure is identified to be the separation column 142, and a message prompting replacement of the separation column 142 is displayed as in the case of the reactor 152, and the separation is performed. When the column 142 is replaced, the subsequent detection can be appropriately performed. Note that the switching of the guard columns 132 and 133 may be performed after the attempt to disconnect the reactor 152 is performed, that is, the guard columns 132 and 133 may be sequentially confirmed from the downstream side.

  As described above, the cause of the defect is automatically specified or the defect is avoided, so that the inspection can be promptly continued. Further, there is no need for the analysis operator to be aware of an appropriate pump pressure.

  It should be noted that the present invention is not limited to providing two guard columns 132 as described above, and it is also possible to provide only one guard column 132 and replace the guard column 132 by a user when there is a defect, similarly to the separation column 142 and the reactor 152. . On the other hand, three or more wires may be provided so that they can be sequentially switched and used. Also, the number of the separation column 142 and the reactor 152 is not necessarily limited to one, and a plurality of the separation columns 142 and the reactor 152 may be automatically switched.

  When the six-way valves 131 to 151 are switched as described above, the flow rate of the pump may be controlled so as to prevent a sudden increase in the pump pressure.

  If the cause of the problem cannot be identified even after performing the above-mentioned operations, for example, an inquiry to a specialist is automatically made via a communication means such as the Internet, or a telephone service is provided. A guidance display for prompting an inquiry by a call, mail transmission, or the like may be displayed.

(Detection and avoidance of defects by analyzing chromatograms)
The detection of a defect in the analysis is not limited to be performed using the sensor such as the pressure sensor 113 as described above. For example, after performing one or more measurements, the resulting chromatogram is analyzed to perform a chromatographic performance index. Or may be performed by obtaining Further, the operation for specifying the cause of the failure or the operation for avoiding the failure may be an operation for setting various device setting parameters set in the device for measurement. Examples of the chromatographic performance index include, for example, separation degree, separation coefficient, theoretical plate number, peak area, peak height, peak width, retention time, hold-up time, retention coefficient, theoretical plate number equivalent height, column pressure loss, Symmetry coefficients, peak valley ratios, SN ratios, baseline noise, baseline drift, detection limits, quantification limits, accuracy, accuracy, and the like can be applied. In particular, for example, the degree of separation performance including at least one of the degree of separation of the components, the separation coefficient, the number of theoretical plates, the height corresponding to the number of theoretical plates, and the peak width can be applied. Further, as the device setting parameters, hardware settings, for example, gradient elution time program, eluent switching timing, eluent composition, flow rate, injection amount, sample dilution ratio, column temperature, column temperature switching timing, Column selection, reaction temperature, reaction reagent composition, detection wavelength, detection wavelength switching timing, response time constant, and the like can be applied. In particular, for example, elution conditions including at least one of the above-described eluent switching timing, gradient elution time program, column temperature switching timing, and flow rate can be applied.

  Thus, the apparatus can be changed so that the measurement operation is performed under the optimum condition. Further, for example, when a plurality of samples of the same composition are mounted on the autosampler for repeated measurement, etc., when the first measurement result is analyzed and the above-described problem is detected, the setting is changed. Subsequent measurement may be performed. In that case, the measurement may be repeated by announcing that the device has changed the setting. Further, the condition change may be instructed to the measurer.

  It is also possible to determine whether the set conditions are inadequate or whether the set conditions are satisfied but the device side is not operating as such for some reason, and perform an operation according to the determined conditions. Good. That is, for example, when the degree of separation is lower than the threshold value (specifically, for example, when the degree of separation between Ala and Cys is less than 1.2), this is mostly due to inadequate setting conditions, but the setting conditions are met. However, there is also a possibility that the number of theoretical plates of the separation column, which is a component of the apparatus, is reduced. In such a case, not only the degree of separation but also the theoretical plate number of the separation column is added to the determination index, and it can be determined whether the condition is inadequate or the apparatus is used. Therefore, if the condition is not satisfactory, the setting condition is changed. On the other hand, if the number of theoretical peaks of an isolated peak such as Gly is less than 3,000, it is determined that the device is attributable to the device, and the fact is displayed as an estimated factor attributable to the device. Alternatively, a trouble avoidance operation such as a (separation) column switching operation may be performed.

(Avoid separation failure 1)
When the chromatogram obtained as a result of the detection by the detector 160 is analyzed and it is detected that the degree of separation of the predetermined component is not appropriate, the switching timing of the eluent is controlled as shown in Table 1 above. In this way, it is possible to automatically avoid poor separation.

  Specifically, for example, when an amino acid is analyzed using a gradient method, the degree of separation between alanine (Ala) and cystine (Cys) is 1.0 or less, as shown in FIG. If an early peak state, which is at least one of the peak time difference t1 between alanine (Ala) and cystine (Cys) being equal to or less than a predetermined value, is detected, the control of the valve 111 delays the switching timing of the eluent. Is done. On the other hand, as shown in FIG. 3B, the degree of separation between cystine (Cys) and valine (Val) is 1.0 or less, or the peak time difference t2 between alanine (Ala) and cystine (Cys) is greater than a predetermined value. If at least one of the rate peak states is detected, the switching timing of the eluent is advanced by controlling the valve 111. By performing such control, the peak time difference t3 between alanine (Ala) and cystine (Cys) can be made appropriate as shown in FIG.

(Avoid separation failure 2)
The effect of the column temperature on the retention time of each component contained in the sample differs for each component. For example, as shown in FIG. 4, Glu has a greater increase in retention time when the column temperature is lower than AspNH2 and GluNH2. Therefore, in the same manner as the above (Avoidance of poor separation degree 1), when it is detected by analysis of the chromatogram obtained as a detection result of the detector 160 that the separation degree of a predetermined component is not appropriate, the column thermostat is used. By controlling the set temperature of 144, it is possible to specify the cause of the separation failure and to automatically avoid the separation failure.

(Avoidance of poor separation 3)
Further, as shown in FIG. 5, for example, by switching the timing of switching the set temperature of the column thermostat 144 from 40 ° C. to 70 ° C. from 63 minutes to 48 minutes after a predetermined reference time, mainly, only the holding time of Trp is reduced. It can be shortened to avoid poor separation.

(Avoid separation failure 4)
For example, as shown in FIG. 6, the composition of the eluent is changed from B4 = 100% to B1 / B4 = 60/40% for 66 to 72 minutes after the predetermined reference time, so that NH3 and Hylys (and Poor separation of its isomer) can be avoided.

(Avoid separation failure 5)
For example, as shown in FIG. 7, the composition of the eluent is changed from B4 = 100% to B2 / B4 = 20/80% from 85% to 98 minutes after the predetermined reference time, so that 3Mehis, Ans and Car are changed. Can be avoided.

(Avoid peak height failure)
Based on the analysis of the chromatogram obtained as a result of detection by the detector 160, for example, an example in which it is detected that the peak height of aspartic acid (Asp) is not appropriate is based on the flowchart of FIG. 8 and the above (Table 1). explain.

  (S101) First, prior to the analysis, a reference value R of the peak height when aspartic acid (Asp) of the standard sample is detected is read from a database or the like (not shown).

  (S102) When the sample is analyzed, the peak height H is measured based on the chromatogram of the analysis result.

  (S103) It is determined whether the measured peak height H is less than, for example, 0.7 times the reference value R. If not, the process proceeds to (S112) and, for example, a measurement completion display is performed. The measurement operation is completed.

  (S104) On the other hand, if the peak height H is smaller than, for example, 0.7 times the reference value R, it is determined whether the automatic purging of the autosampler (AS) 120 has been performed.

  (S105) When it is determined in the above (S104) that the automatic purging has not been performed, after performing the automatic purging, the process returns to (S102), and the analysis is performed again to measure the peak height H and thereafter. Is repeated. That is, avoidance of the peak height failure is attempted, and if it is avoided, the process proceeds to (S112) as described above, and the measurement operation is completed.

  (S106) On the other hand, if the automatic purging has already been performed, the date of replacement of the ninhydrin reagent is firstly read, for example, to guide the user to another workaround.

  (S107) It is determined whether two weeks or more have passed since the date of replacement of the ninhydrin reagent.

  (S108) If two weeks or more have elapsed since the date of replacement of the ninhydrin reagent, a message prompting the user to replace is displayed, and the measurement operation ends.

  (S109) When two weeks or more have not passed since the exchange date of the ninhydrin reagent, it is further determined whether one month or more has passed since the preparation of the standard sample.

  (S110) If one month or more has passed since the adjustment of the standard sample, a message prompting the user for a new standard adjustment sample is displayed, and the measurement operation ends.

  (S111) On the other hand, if one month has not passed since the adjustment of the standard sample, other factors are assumed, and for example, a display indicating an abnormal state of the apparatus is displayed, and the measurement operation ends. In the case where such unknown factors are assumed, for example, it is possible to automatically make an inquiry to a specialist through communication means such as the Internet, or to make a service call or e-mail transmission by telephone. May be displayed for prompting an inquiry.

  When it is determined in the above (S103) that the peak height H is, for example, less than 0.7 times the reference value R, the automatic purging of the autosampler 120 is always performed, and the analysis is performed again. The measurement operation may be terminated after checking other factors or the like after (S106) without automatically performing the measurement.

  As described above, when various inaccuracies in the sample analysis are detected and the operation for identifying the cause of the inconvenience and the operation for avoiding the inconvenience are performed, so that the chromatograph does not operate properly. Can be easily handled.

Reference Signs List 100 Liquid chromatograph 110 Pump 111 Valve 112 Eluent tank 113 Pressure sensor 120 Autosampler 131 Hexagonal valve 132/133 Guard column 141 Hexagonal valve 142 Separation column 143 Temperature sensor 144 Column thermostat 151 Hexagonal valve 152 Reactor 160 Detector 170 Control unit 170a Inference engine 170b Knowledge data storage unit 170c Communication unit

Claims (10)

A chromatograph for supplying an eluent and a sample, analyzing the sample by separating and detecting components contained in the sample,
A detection unit that detects a defect in the analysis,
An operation control unit that causes the component related to the analysis to perform at least one of the operation for identifying the cause of the failure or the operation for avoiding the failure,
A chromatograph comprising: The chromatograph of claim 1, wherein
The operation for identifying the cause of the defect or the operation for avoiding the defect is an operation for selectively releasing a component related to the analysis or switching to another component. Graph. It is a chromatograph of any one of Claim 1 and Claim 2,
The above components related to the above analysis include:
A pump for sending an eluent,
A pressure sensor for detecting the pressure on the discharge side of the pump,
At least two of a guard column, a precolumn, a separation column, and a reactor;
Including
The detection unit detects that the pressure detected by the pressure sensor is equal to or higher than a predetermined value,
The operation control unit, when the detection pressure equal to or higher than the predetermined value is detected, sequentially disconnects the guard column, the precolumn, the separation column, or the reactor from the downstream side or the upstream side, and specifies a factor of the detection pressure increase. A chromatograph characterized in that: The chromatograph of claim 3, wherein
Multiple guard columns or pre-columns,
A switching valve for selectively switching the plurality of guard columns or pre-columns,
The chromatograph, wherein the operation control unit switches any guard column or pre-column to another guard column or pre-column. The chromatograph of claim 1, wherein
Based on the detection results of the components contained in the sample, the detection unit detects a defect in the analysis by using a chromatographic performance index for the components,
The chromatograph, wherein the operation control unit controls an apparatus setting parameter in the analysis or performs an operation of switching a component related to the analysis to another component according to the detection result. The chromatograph of claim 5, wherein
The above-mentioned chromatographic performance index includes the degree of separation, the separation coefficient, the number of theoretical plates, the peak area, the peak height, the peak width, the retention time, the hold-up time, the retention coefficient, the height equivalent to the number of theoretical plates, the column pressure loss, the symmetry coefficient, At least one of a peak valley ratio, a signal-to-noise ratio, a baseline noise, a baseline drift, a detection limit, a quantification limit, accuracy, and accuracy;
The above device setting parameters include a gradient elution time program, an eluent switching timing, an eluent composition, a flow rate, an injection amount, a sample dilution ratio, a column temperature, a column temperature switching timing, a column select, a reaction temperature, a reaction reagent composition, a detection wavelength, A chromatograph characterized by at least one of a detection wavelength switching timing and a response time constant. The chromatograph of claim 5, wherein
While being configured to be able to switch and supply multiple eluents,
The detection unit detects a degree of separation performance based on a detection result of a component contained in the sample,
A chromatograph, wherein the operation control section controls elution conditions. 8. The chromatograph of claim 7, wherein:
Configured to analyze amino acids,
The detection unit,
An early peak state in which the degree of separation between alanine and cystine is equal to or less than a predetermined value, or the peak time difference between alanine and cystine is equal to or less than a predetermined value, and the degree of separation between cystine and valine is equal to or less than a predetermined value, or Detecting a rate peak state that is at least one of the peak time difference between alanine and cystine is not less than a predetermined value,
The chromatograph, wherein the operation control unit delays the timing of switching the predetermined eluent in the early peak state, and advances the timing of switching the predetermined eluent in the rate peak state. The chromatograph of claim 1, wherein
The components according to the analysis include an autosampler having an automatic purging function,
The detection unit detects a detection failure in which the ratio between the detected peak height of the predetermined component and the reference value of the peak height of the standard sample is equal to or less than a predetermined value,
The chromatograph, wherein the operation control unit causes the autosampler to perform automatic purging when the detection failure occurs. 10. The chromatograph of claim 9, wherein:
Configured to analyze amino acids,
The chromatogram is characterized in that the detection failure is such that the ratio of the detected peak height of aspartic acid to the reference value of the peak height of the standard sample is not more than a predetermined value.

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